Diazo compounds, accessed directly from parent azides, are extremely versatile dipoles in 1,3-dipolar cycloaddition reactions with a cyclooctyne. The reactivity of each diazo compound, unlike the analogous azide, is critically dependent on its electronic structure. The rate constants for the reaction of the azides differ only two fold.  In contrast, those for the diazo compounds vary by a factor of a thousand. The relative rate constants for each azide and diazo pair are predictable using frontier molecular orbital theory. The diazo compounds, unlike the complimentary azides, displayed a large rate enhancement moving from aprotic to protic solvents. The most reactive diazo compound exhibited the highest known second-order rate constant to date for a dipolar cycloaddition with a cycloalkyne. Importantly, the diazo compounds are stable at neutral pH in the presence of cysteine or glutathione. These data provide a new modality for effecting chemoselective reactions in a biological setting.

Diazo compounds as highly tunable 1,3-dipoles for cycloaddition reactions with cyclooctynes

245th National Meeting (2013)

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